Renal dysfunction or disease includes acute renal failure and chronic renal failure. In general, renal diseases are characterized by one or more of the following: reduced renal blood flow, reduced glomerular filtration rate, proteinuria, hematuria and alterations in water and sodium excretion.
Acute renal failure is a condition characterized by an abrupt and sustained reduction in glomerular filtration rate (GFR) occuring within a period of hours in response to an acute ischemic or nephrotoxic insult. Acute renal failure is not immediately reversible when the initial disturbance has been eliminated. Immediate improvment in GFR and increasing fluid flow through the nephron appears to be of critical importance in the prognosis of acute renal failure.
Chronic renal failure is characterized by (1) a reduction in GFR that has been evident for 3 to 6 months, (2) a continual decline in GFR over a period of years and (3) symptoms of uremia. The term renal insufficiency is often used to characterize a condition in which a mild reduction in GFR has occurred, but no uremic symptoms have appeared. Chronic renal failure denotes irreversible nephron loss, wheras acute renal failure reflects a reduction in single nephron GFR due to potentially reversible nephron injury.
Proteinuria (elevated urinary excretion of plasma proteins) can be present during acute and chronic renal failure and has been shown to be an accurate index of the extent of glomerular damage (Dennis, et al., in The Kidney: Physiology and Pathophysiology, edited by D. W. Seldin and G. Giebisch, Vol. 2, pp. 1805-1818, Raven Press, N.Y., 1985). Agents that reduce proteinuria have been shown to have beneficial effects on glomerular injury (Anderson, et al., J. Clin. Invest. 76 612 (1985)).
It is believed that angiotensin II plays a role in renal failure. Angiotensin II (AII) is a peptide hormone that is produced in the kidney in a two step process, the first step of which is the cleavage of angiotensinogen by the enzyme renin. Renin is stored primarily in the juxtaglomerular cells of the kidney.
Angiotensin II has profound effects on the kidney, including direct vasoconstriction of the renal vascular bed thereby altering renal blood flow, stimulation of sodium reabsorption, modification of glomerular feedback, alteration of GFR through changes in either the hydraulic pressure or by reducing the filtration surface area secondary to mesangial cell contraction, and increasing distal nephron sodium reabsorption indirectly through stimulation of aldosterone secretion. In addition, AII increases the passage of circulation macromolecules into the glomerular mesangium and decreases their egress. All of these effects of angiotensin II have a negative impact on renal disease. Therefore, an agent that prevents or inhibits the formation of angiotensin II, such as a renin inhibitor, can have a beneficial effect on renal disease. Renin inhibitors have been disclosed as agents for treating systemic hypertension and there are no known side effects which result when renin is inhibited from acting on its substrate.